Targeting necroptosis: how does exercise protect against metabolic dysfunction-associated fatty liver disease?

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic metabolic disease that poses a serious threat to global health. If left untreated, it may progress to metabolic dysfunction-associated steatohepatitis (MASH), ultimately leading to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Clarifying the underlying mechanisms of MASLD is therefore essential for both prevention and treatment. Although the pathophysiology of MASLD still remain incompletely understood, accumulating evidence supports a role for necroptosis in its development. In parallel, exercise is well established to improve metabolic dysfunction, hepatic steatosis, and inflammation associated with MASLD. Emerging studies further suggest that exercise can modulate signaling pathways related to necroptosis in various tissues. However, it should be emphasized that direct experimental evidence demonstrating that exercise alleviates MASLD specifically through regulating of hepatic necroptosis is currently lacking. Most of the proposed links between exercise and necroptosis in the context of MASLD are therefore based on indirect evidence derived from non-hepatic models or from independent lines of research and should be considered biologically plausible but not yet causally established mechanisms. In this review, we summarize current evidence supporting the involvement of necroptosis in MASLD, as well as evidence for the metabolic and anti-inflammatory effects of exercise. We then discuss potential mechanisms-including the RIPK1/RIPK3, AMPK/mTOR, and cGAS/STING pathways-through which exercise may influence MASLD in relation to necroptosis, while clearly distinguishing between evidence-supported findings and hypothesis-driven interpretations. Overall, this review proposes a conceptual framework linking exercise, necroptosis, and MASLD, but also highlights that this framework remains hypothesis-driven and requires direct experimental validation, particularly in hepatic models.